Patr�cia F. Monteiro
Synthesis of micellar-like terpolymer nanoparticles with reductively-cleavable cross-links and evaluation of efficacy in 2D and 3D models of triple negative breast cancer
Monteiro, Patr�cia F.; Gulfam, Muhammad; Monteiro, C�ntia J.; Travanut, Alessandra; Abelha, Thais Fedatto; Pearce, Amanda K.; Jer�me, Christine; Grabowska, Anna M.; Clarke, Philip A.; Collins, Hilary M.; Heery, David M.; Gershkovich, Pavel; Alexander, Cameron
Authors
Muhammad Gulfam
C�ntia J. Monteiro
Alessandra Travanut
Thais Fedatto Abelha
Amanda K. Pearce
Christine Jer�me
ANNA GRABOWSKA ANNA.GRABOWSKA@NOTTINGHAM.AC.UK
Professor of Cancer Microenvironment
Philip A. Clarke
HILARY COLLINS HILARY.COLLINS@NOTTINGHAM.AC.UK
Scientific Officer
DAVID HEERY david.heery@nottingham.ac.uk
Professor of Eucaryotic Gene Regulation
PAVEL GERSHKOVICH PAVEL.GERSHKOVICH@NOTTINGHAM.AC.UK
Associate Professor
Professor CAMERON ALEXANDER CAMERON.ALEXANDER@NOTTINGHAM.AC.UK
Professor of Polymer Therapeutics
Abstract
© 2020 Elsevier B.V. Triple negative or basal-like breast cancer (TNBC) is characterised by aggressive progression, lack of standard therapies and poorer overall survival rates for patients. The bad prognosis, high rate of relapse and resistance against anticancer drugs have been associated with a highly abnormal loss of redox control in TNBC cells. Here, we developed docetaxel (DTX)-loaded micellar-like nanoparticles (MLNPs), designed to address the aberrant TNBC biology through the placement of redox responsive cross-links designed into a terpolymer. The MLNPs were derived from poly(ethyleneglycol)-b-poly(lactide)-co-poly(N3-α-ε-caprolactone) with a disulfide linker pendant from the caprolactone regions in order to cross-link adjacent chains. The terpolymer contained both polylactide and polycaprolactone to provide a balance of accessibility to reductive agents necessary to ensure stability in transit, but rapid micellar breakdown and concomitant drug release, when in breast cancer cells with increased levels of reducing agents. The empty MLNPs did not show any cytotoxicity in vitro in 2D monolayers of MDA-MB-231 (triple negative breast cancer), MCF7 (breast cancer) and MCF10A (normal breast epithelial cell line), whereas DTX-loaded reducible crosslinked MLNPs exhibited higher cytotoxicity against TNBC and breast cancer cells which present high intracellular levels of glutathione. Crosslinked and non-crosslinked MLNPs showed high and concentration-dependent cellular uptake in monolayers and tumour spheroids, including when assessed in co-cultures of TNBC cells and cancer-associated fibroblasts. DTX loaded crosslinked MLNPs showed the highest efficacy against 3D spheroids of TNBC, in addition the MLNPs also induced higher levels of apoptosis, as assessed by annexin V/PI assays and increased caspase 3/7 activity in MDA-MB-231 cells in comparison to cells treated with DTX-loaded un-crosslinked MLNP (used as a control) and free DTX. Taken together these data demonstrate that the terpolymer micellar-like nanoparticles with reducible crosslinks have high efficacy in both 2D and 3D in vitro cancer models by targeting the aberrant biology, i.e. loss of redox control of this type of tumour, thus may be promising and effective carrier systems for future clinical applications in TNBC.
Citation
Monteiro, P. F., Gulfam, M., Monteiro, C. J., Travanut, A., Abelha, T. F., Pearce, A. K., …Alexander, C. (2020). Synthesis of micellar-like terpolymer nanoparticles with reductively-cleavable cross-links and evaluation of efficacy in 2D and 3D models of triple negative breast cancer. Journal of Controlled Release, 323, 549-564. https://doi.org/10.1016/j.jconrel.2020.04.049
Journal Article Type | Article |
---|---|
Acceptance Date | Apr 29, 2020 |
Online Publication Date | May 3, 2020 |
Publication Date | Jul 10, 2020 |
Deposit Date | May 12, 2020 |
Publicly Available Date | Mar 29, 2024 |
Journal | Journal of Controlled Release |
Print ISSN | 0168-3659 |
Electronic ISSN | 1873-4995 |
Publisher | Elsevier |
Peer Reviewed | Peer Reviewed |
Volume | 323 |
Pages | 549-564 |
Series ISSN | 0168-3659 |
DOI | https://doi.org/10.1016/j.jconrel.2020.04.049 |
Keywords | Pharmaceutical Science |
Public URL | https://nottingham-repository.worktribe.com/output/4395597 |
Publisher URL | https://www.sciencedirect.com/science/article/abs/pii/S0168365920302637 |
Files
Paper MLNPs JCR Clean
(1.9 Mb)
PDF
Synthesis of micellar-like terpolymer
(2 Mb)
PDF
You might also like
Synthesis of Passerini-3CR Polymers and Assembly into Cytocompatible Polymersomes
(2020)
Journal Article
Downloadable Citations
About Repository@Nottingham
Administrator e-mail: digital-library-support@nottingham.ac.uk
This application uses the following open-source libraries:
SheetJS Community Edition
Apache License Version 2.0 (http://www.apache.org/licenses/)
PDF.js
Apache License Version 2.0 (http://www.apache.org/licenses/)
Font Awesome
SIL OFL 1.1 (http://scripts.sil.org/OFL)
MIT License (http://opensource.org/licenses/mit-license.html)
CC BY 3.0 ( http://creativecommons.org/licenses/by/3.0/)
Powered by Worktribe © 2024
Advanced Search